Calcium-dependent changes of the myocardial contractile function at chronic adriamycin treatment.

The contractile function of hearts and atria isolated from rats treated with adriamycin (ADM, total cumulative dose 16-20 mg/kg for 8-10 weeks) was moderately lower as compared to control preparations. However, the former exhibited a relatively higher positive inotropic response to an elevation of Ca++ concentration in the perfusate of isolated hearts or paired pulse stimulation of atria so that maximally attainable values were similar in both groups. On the contrary, the depression of ADM-treated atrial contractile amplitude became even more prominent at moderate increase in stimulation rate and was associated with the apparent incomplete relaxation. Chemically skinned fibers from ADM-treated hearts began to develop force at lower Ca++ concentration and exhibited higher Ca++-sensitivity in pCA range 5.8-5.4. Results suggest that long-term ADM-treatment may be associated with a functional deficiency of Ca++-transporting mechanisms in myocardial cells which may contribute to the depression of the cardiac contractile function.

[Myocardial diastolic elasticity in chronic adriamycin lesion]. / Diastolicheskaia uprugost' miokarda pri khronicheskom adriamitsinovom porazhenii.

Isolated hearts of the majority of rats receiving 20 mg/kg adriamycin for 10 weeks exhibited normal pump function. Left ventricular diastolic stiffness of these hearts was approximately 1.5 times higher, as compared to control hearts, with the filling pressure in the range of 5 to 20 cm H2O and diastolic pause 23% longer due to bradycardia. Pacing-induced increase in the heart rate up to the control level resulted in further increase in left ventricular diastolic stiffness due to the rise in myocardial stiffness, associated with a fall in cardiac output by 36%. The heart and right atrial compliance determined in separate experiments did not differ significantly from the control. The results suggest that increased left ventricular diastolic stiffness of adriamycin-treated rats seems to be rather due to energy-dependent disturbance in myofibril relaxation than to usually arising myocardial fibrosis.

[Autoregulation of the contractile function of the myocardium in response to changes in the concentration of the activating cation]. / Samoreguliatsiia sokratitel'noi funktsii miokarda pri izmenenii kontsentratsii aktiviruiushchego kationa.

In guinea-pig isolated papillary muscles, dependence of the isotonic contraction velocity on the perfusate Ca++ concentration was studied. The dependence was the steepest at the lowest rate of stimulation. At a high rate (2 Hz), changes in contraction velocity as well as in extent of the muscle shortening were minimal. Replacement of a half of Ca++ ions by Sr++ resulted in an augmentation of steepness of the dependence on sum of [Ca++] and [Sp++], and in a more prominent fall in relaxation velocity as compared with contraction velocity. Replacement of a half of Ca++ ions with Ba++ or depletion of [Na+] in usual solution to 25 mM resulted in a prominent fall in relaxation velocity while the contraction velocity increased. This dissociation coincided with signs of cellular Ca++ overload and a more steep restitution of contraction velocity during diastole. Results are discussed in terms of participation of Na+-Ca++ exchange in these self-regulatory phenomena.

[Increase in the maximum intensity of myocardial contractile function using glutamic acid]. / Povyshenie maksimal'noi intensivnosti sokratitel'noi funktsii miokarda glutaminovoi kislotoi.

In experiments on 54 isolated papillary muscles from guinea-pig hearts a rise in contraction velocity and amplitude was induced by the increment in stimulation rate. Maximal contractile indices and the rate at which they were observed were the less the greater the muscle thickness limiting oxygen supply. At any rate the relaxation velocity of thin muscles (cross sectional area 0.38 mm2) was approximately twice higher than the contraction velocity. The difference became smaller as the muscle thickness increased and completely disappeared in experiments on thick muscles (cross sectional area 1.34 mm2). Addition of glutamic acid (3.5 mM) to perfusate did not influence contraction and relaxation values at a rate of 0.5-2.0 Hz but prevented their depression at a rate of 2.5-3.5 Hz, which was typical of thick muscles. This effect seems to be related to improved energy production by myocardial cells during hypoxia or ischemia.

[Effect of calmodulin inhibitors on the contraction and relaxation of the heart muscle]. / Vliianie ingibitorov kal'modulina na sokrashchenie i rasslablenie serdechnoi myshtsy.

The calmodulin inhibitor trifluoroperazine (5 microM) diminished the velocity of contraction and relaxation of the guinea-pig papillary muscle by 31 and 53%, respectively. Methophenazine showed approximately the same affinity to both calmodulin and trifluoroperazine and nearly 40-fold less affinity to troponin. Methophenazine (5 microM) did not change the contraction velocity and diminished the relaxation velocity ty 21%. It is suggested that calmodulin participates mainly in the control of myocardial relaxation.

[Cationic regulation of myocardial contraction and relaxation when contraction frequency is increased]. / Kationnaia reguliatsiia sokrashcheniia i rasslableniia miokarda pri uvelichenii chastoty sokrashchenii.

During augmentation of frequency of contractions or Ca2+ perfusate concentration the velocity of isotonic relaxation increased much more than the velocity or amplitude of contraction. The phenomenon of predominant activation of relaxation ( PPAR ) was less prominent at decreased Ca2+ concentration acidosis (pH 6,85), under action of calmodulin inhibitor, trifluoperazine, or replacement of Ca2+ ions by Sr2+. Diminution of Na2+ concentration to 25 mM was followed by apparent signs of cellular Ca2+--overload and elimination of PPAR . The results coincide with the suggestion that PPAR is caused by activation of calmodulin-dependent Ca2+ removal from the myoplasma and myofibrils.

[Effect of acidosis on Ca2+ binding by the sarcoplasmic reticulum and on relaxation of the cardiac muscle]. / Vliianie atsidoza na pogloshchenie Ca2+ sarkoplazmaticheskim retikulumom i rasslablenie serdechnoi myshtsy.

A value of Ca2+ binding in 1 second by sarcoplasmic reticulum fragments from guinea pig hearts increased proportionally to elevation of Ca2+ concentration from 0.1 to 3.0(-6) M at pH 7.2. Decline of pH to 6.8 and 6.2 decreased the Ca2+ bound in 1 second, but increased the Ca2+ bound in 30 seconds when membrane permeability has become a crucial factor in determining Ca2+ bound. In experiments on guinea pig papillary muscles, a decline of pH from 7.35 to 6.83 resulted in a nearly equal fall in velocities of isometric contraction and relaxation (27 and 21%, respectively), but during isotonic shortening when the relaxation proceeds much faster, a fall in relaxation velocity (44 +/- 3%) was significantly more profound as compared to the fall in contraction velocity (29 +/- 4%). This effect as well as a decrease in initial rate of Ca2+ binding by sarcoplasmic reticulum suggest a direct inhibitory effect of acidosis on Ca2+ removal from myofibrils in myocardial cells.

[Effect of increased mechanical loading on the relation between the contraction of isolated cardiac muscle and the concentration of Ca++ in the perfusate]. / Vliianie povyshennoi mekhanicheskoi nagruzki na zavisimost' sokrashcheniia izolirovannoi serdechnoi myshtsy ot kontsentratsii Ca++ v perfuzate.

The distension of isolated papillary muscles working isotonically or a transition to isometric working entailed an increased sensitivity of the contractile velocity to changes in perfusate Ca++ concentration. After sudden fall in Ca++ concentration, a more rapid decline of the contractile velocity in isometric mode was observed as compared to isotonic mode of working. The similar difference was found in experiments on isolated guinea pig heart working in isovolumic or auxotonic modes, though the rate of Ca++ loss by the heart was the same. The results suggest that an increased mechanical load may diminish the ability of myocardial cells to compensate for the changes in external Ca++.

[Effect of thyrocalcitonin on the contraction and relaxation of the isolated myocardium in metabolic blockade and acidosis]. / Vliianie tirokal'tsitonina na sokrashchenie i rasslablenie izolirovannoi serdechnoi myshtsy pri metabolicheskoi blokade i atsidoze.

Thyrocalcitonine did not produce any effect on the contraction and relaxation of the thin papillary muscles of guinea-pigs, but restored reduced indices of the thick muscles function. The effect of the hormone was most expressed at a high contraction rate. The hormone also stopped reduction in the amplitude of the contractions or partly restored it under the action of metabolic inhibitors--2.4-dinitrophenol or 2-deoxyglucose as well as under the action of acidosis (pH-6.9). A positive inotropic effect of the hormone, that manifest itself under the conditions of a reduced amplitude of contractions is evidently realized through the influence on the Ca++--Na+ metabolism in cells and physiologically grounded, since it favours the stabilization of the myocardial contractility under hypocalcemia.

[Effect of emotional-pain stress on the contractile function and sensitivity to noradrenaline of cardiac muscle]. / Bliianie emotsional'no-bolevogo stressa na sokratitel'nyiu finktsiiu i adrenoreaktivnost' serdechnoi myshtsy.

The effect of variations in the Ca concentration in the perfusate on the function of isolated hearts of control rats and of those who sustained the emotional-pain stress (EPS) was studied. It was found that the EPS sharply increased the cardiac response in the animals to shifts in the Ca concentration. A rise in the main parameters of the cardiac contractile function in response to an increased Ca concentration was more pronounced in rats after the EPS than in the controls. The sensitivity to noradrenaline decreased 2-fold as compared to the control animals. It is suggested that the growth of the relationship between the cardiac function and the Ca concentration in the animals after the EPS is caused by the damaged membranous mechanisms of Ca transport in the myocardial cells.

[Effect of hypokinesia on the contractile function of the myocardium]. / Vliianie gipokinezii na sokratitel'nuiu funktsiiu serdechnoi myshtsy.

Rats were subjected to hypokinesia for two months and the contractile function of isolated papillary muscles was studied. Hypokinesia reduced significantly the isotonic contraction velocity which depended on the ATPase activity of the myofibrils; it also reduced the velocity and index of relaxation which depended on the functional capacity of the Ca++-pump of the sarcoplasmic reticulum. The maximum force of isometric contraction determined by the quantity of actomyosine bridges in the myofibrils did not change after hypokinesia. This complex of changes is contrary to that observed in adaptation to exercise, when the velocity of isotonic contraction and relaxation increases while the force of isometric contraction does not change. The possible mechanism of this stability of the contractile force during adaptation and readaptation of the heart is discussed.

[Effect of hypokinesia on the contractile function and nervous regulation of the heart]. / Vliianie gipokinezii na sokratitel'nuiu funktsiiu i nervnuiu reguliatsiiu serdtsa.

Prolonged hypokinesia caused cardiac deadaptation in rabbits which resulted in diminishing of the left ventricle speed of contraction and relaxation joined later by a decreased vascular resistance. As a result, the ejection velocity as well as the stroke volume and the cardiac output were normal. The decrease of the relaxation speed became more obvious at a high heart rate and resulted in shortening of the diastolic pause and diminishing of cardiac output. Hearts of the hypokinetic animals were characterized by normal maximal pressure developed by a unit of myocardial mass at aorta clamping, decrease adrenoreactivity, and increased cholinoreactivity. This complex of changes is contrary to changes observed in adaptation to exercise, but is similar to changes observed in the compensatory hypertrophy of the heart.

[Contractile function of the heart and its reactivity to noradrenaline in the process of the bodies adaptation to moderate altitudes]. / Sokratitel'naia funktsiia serdtsa i ego reaktivnost' k noradrenalinu v protsesse adaptatsii organizma k srednegor'iu.

In acute experiments on rats adapted for 4 weeks to the altitude of 2100 m it was found that at the early period of altitude adaptation the left ventricular systolic pressure and the maximal rates of pressure rise and fall considerably exceeded the values of control tests conducted in Moscow. Later on the parameters of the cardiac contractile function stabilized gradually. In 4 weeks the heart of adapted animals showed a greater increment of the contractility parameters in response to noradrenaline injection and a higher stability of the contractile function at very high heart rates.